The nuclear receptor superfamily, which includes steroid hormone receptors, are small chemical ligand-inducible transcription factors which have been shown to play roles in controlling development, differentiation and physiological function. Isolation of cDNA clones encoding nuclear receptors reveals several characteristics. First, the NH2-terminal regions, or the A/B domain, which vary in length between receptors, are hypervariable with low homology between family members. There are three internal regions of conservation, referred to as domains C, D and E/F. Region C encodes a cysteine-rich region which is referred to as the DNA binding domain (DBD). Regions D and E/F are within the COOH-terminal section of the protein. Region D encodes the hinge domain which is also referred to as the ligand binding domain (LBD). For a review, see Power et al. (1992, Trends in Pharmaceutical Sciences 13: 318–323).
The lipophilic hormones that activate steroid receptors are known to be associated with human diseases. Therefore, the respective nuclear receptors have been identified as possible targets for therapeutic intervention. For a review of the mechanism of action of various steroid hormone receptors, see Tsai and O'Malley (1994, Annu. Rev. Biochem. 63: 451–486).
Recent work with non-steroid nuclear receptors has also shown the potential as drug targets for therapeutic intervention. This work reports that peroxisome proliferator activated receptor g (PPARg), identified by a conserved DBD region, promotes adipocyte differentiation upon activation and that thiazolidinediones, a class of antidiabetic drugs, function through PPARg (Tontonoz et al., 1994, Cell 79: 1147–1156; Lehmann et al., 1995, J. Biol. Chem. 270(22): 12953–12956; Teboul et al., 1995, J. Biol. Chem. 270(47): 28183–28187). This indicates that PPARg plays a role in glucose homeostasis and lipid metabolism.
Mangelsdorf et al. (1995, Cell 83: 835–839) provide a review of known members of the nuclear receptor superfamily.
U.S. Pat. No. 5,614,620, issued to Liao and Chang on Mar. 25, 1997, discloses nucleotide sequences encoding human and rat androgen receptor, along with the complete amino acid sequence within the open reading frame of the respective androgen receptor.
EP 0 365 657 B1 issued to French et al. Aug. 4, 1999, discloses a recombinant DNA molecule encoding a human androgen receptor, along with the amino acid sequences of human androgen receptor protein.
Choong et al. (1998, J. Mol. Evol. 47: 334–342) disclose amino acid sequences for non-human primates such as chimpanzee, baboon, lemur and Macaca fascicularis (see SEQ ID NO:6 for nucleotide sequence, see also Gen Bank Accession No. U94179 for the nucleotide and amino acid sequence of Macaca fascicularis androgen receptor).
Abdelgadir et al. (1999, Biology of Reproduction 60:1251–1256) disclose a PCR fragment representing a 5′ portion of the Macaca mulatta coding region (see also Gen Bank Accession No. AF092930).
It would be advantageous to identify additional genes closely related to the human androgen receptor gene, such as those possessed by nonhuman primates used for pharmacological investigation, which encode an androgen receptor protein. Since the androgen receptor plays an important role in regulating development, reproduction, and maintenance of bone and muscle, such genes, and their expressed functional proteins, will be useful in assays to select for compounds which modulate the biological activity of the androgen receptor, especially as this modulation pertains to bone formation. The present invention addresses and meets these needs by disclosing isolated nucleic acid molecules which encode a full-length Macaca mullata androgen receptor.